Influence of the pKa value on the antioxidant activity of licorice flavonoids under solvent‐mediated effects

Abstract Licorice flavonoids (LCFs) have been widely used in food care and medical treatment due to their significant antioxidant activities. However, the molecular mechanism of their antioxidant activity remains unclear. Therefore, network pharmacology, ADMET, density functional theory (DFT), molecular docking, and molecular dynamics (MD) simulation were employed to explore the molecular mechanism of the antioxidant effects of LCF. The network pharmacology and ADMET studies showed that the active molecules of kumatakenin (p K a = 6.18), licoflavonol (p K a = 6.86), and topazolin (p K a = 6.21) in LCF are key antioxidant components and have good biosafety. Molecular docking and MD simulation studies demonstrated that active molecules interacted with amino acid residues in target proteins to form stable protein–ligand complexes and exert their antioxidant effects. DFT studies showed that the antioxidant activity of LCF could be significantly modulated under the solvent‐mediated effect. In addition, based on the derivation of the Henderson–Hasselbalch and van't Hoff formulas, the functional relationships between the reaction‐free energy (Δ G ) of LCF and the pH and p K a values were established. The results showed that active molecules with larger p K a values will be more conducive to the improvement of their antioxidant activity under solvent‐mediated effects. In conclusion, this study found that increasing the p K a value of LCF would be an effective strategy to improve their antioxidant activity under the effect of solvent mediation. The p K a value of an LCF will be a direct standard to evaluate its solvent‐mediated antioxidant activity. This study will provide theoretical guidance for the development of natural antioxidants.